The Connective Tissue and Diseases Section began studying inflammatory myopathies (polymyositis, dermatomyositis, and related diseases) some years ago in an attempt to understand the relationship of autoantibodies to autoimmune disease. These diseases seemed to offer the best example of autoimmune diseases associated with highly specific disease-related autoantibodies and evidence of a viral etiology. They are very uncommon and hence relatively less studied than other autoimmune diseases, and they are very debilitating and hence in need of improved therapy. In order to attract patients here to allow more detailed clinical, immunological, genetic, and viral studies, we began doing trials of therapy and have completed a number of such studies. They are among the very few published controlled trials in this difficult to treat family of illnesses. Currently, there are three trials in various stages of completion. 1) A randomized crossover trial of high dose intravenous methotrexate and of a combination of oral methotrexate and azathioprine was completed last year and the analysis was completed and prepared for publication this year. The value of the combination therapy, even in patients who had failed to improve in trials of either drug alone, has been clearly established. 2) A pilot trial of the purine analogue, flurodeoxyadenosine, enrolled 14 patients, the last of whom has recently completed the full observation period. This drug, which preferentially affects lymphocytes, is being studied in several autoimmune diseases after an extensive experience in hairy cell leukemia. Analysis of the trial is just underway. If there is evidence of efficacy in a sufficient number of patients, a larger controlled, randomized trial will be undertaken. 3) A pilot trial of the traditional anti-thyroid drug, methimazole, is well underway. The rationale for this trial is the discovery by D. Singer and L. Kohn that this drug down-regulates MHC Class I, and up-regulation of Class I appears to be an important pathogenetic event in myositis. In addition to studying the clinical efficacy of methimazole, there are extensive studies in the laboratory related to this proposed mechanism of action (see Z01 AR 41074-08 ARB).